Rewiring fibrotic signaling using engineered RNA-responsive riboswitches
Description: A central driver of cardiovascular disease progression is fibrosis, in which activated cardiac fibroblasts (CFs) differentiate into myofibroblasts, promoting maladaptive remodeling and heart failure. Effective therapies to prevent fibrosis or halt heart failure progression are limited. Recent advances in single-cell RNA sequencing have identified myofibroblast-enriched transcripts, creating new opportunities for targeted anti-fibrotic strategies. These findings underscore the need for programmable, RNA-responsive platforms capable of sensing disease-relevant transcripts and triggering tailored genetic responses, including selective cell ablation, phenotypic modulation, or lineage reprogramming, while preserving essential fibroblast functions. In this study, we aim to develop a post-transcriptional, non-cell-autonomous transgene cassette using tools from synthetic RNA biology. We focus on engineered translatable circular RNAs (tcRNAs), which offer enhanced stability over linear mRNAs due to exonuclease resistance. Unlike linear mRNAs, tcRNAs lack a 5' cap and depend on internal ribosome entry sites (IRESs), which are often inefficient and poorly tunable. To overcome this limitation, we designed a novel RNA-responsive riboswitch that hijacks the 5' cap from endogenous mRNAs and recruits the translation initiation machinery near the tcRNA start codon, enabling rolling translation and markedly increasing protein output. These innovations establish a foundation for a CF-targeted platform to deliver cardiac reprogramming factors. Our central hypothesis is that tcRNAs can drive robust, conditional expression of cardiogenic factors in activated CFs, enabling their reprogramming into cardiomyocytes and attenuating fibrosis. We propose two aims: (1) to define the mechanism by which tcRNAs engage the translation initiation machinery in response to fibroblast-specific mRNAs, and (2) to develop a tcRNA-based system for sustained, conditional expression of cardiogenic factors in activated CFs. Successful completion of this work will yield a versatile RNA-responsive platform for targeted fibroblast modulation, advancing both anti-fibrotic therapy and cardiac regeneration.
Funder: American Heart Association
Amount: $100,000
Funding type: research
Funder scheme: Bridge Transformational Project Award
Start date: 2026-04-01
End date: 2027-03-31
Investigators: Jialiang Liang, Jialiang Liang
Institution: University of Cincinnati
Funded outputs count: 0
Funder award ID: 26BTPA1622800
OpenAlex ID: G4788092556